The standard procedure commonly used by synthetic organic chemists to alkylate indoles requires the use of an alkyl halide under normal alkylation procedures. However, this procedure works only for lower alkyl groups which exhibit little or no steric hindrance. As the alkyl halides become more substituted or sterically hindered, elimination to the olefin becomes the prevalent reaction, and in many cases is the predominent reaction. See, e.g., Lipshutz et al. in J. Am. Chem. Soc. 103, 7672-7674 (1981) and Veeravagu et al. in J. Am. Chem. Soc. 86, 3072-3075 (1964).
A variety of methods exist for alkylating the nitrogen atom of indole. Cardillo et al. in Tetrahedron, Vol. 23, 3771-3783 (1967) and Kikugawa et al. in Synthesis 461-462 (1981) disclose the N-alkylation of indoles with various halide derivatives. Plieninger in Chem. Ber. 87, 127-128 (1954) disclose the alkylation of indole with benzyl chloride and benzyl p-toluenesulfonate. Shirley et al. in J. Am. Chem. Soc. 75, 375-378 (1953) disclose the synthesis of 1-methylindole by reacting indole with methyl p-toluenesulfonate. These processes do not relate to more complex substrates or substituents which are prone to elimination.
Procedures for alkylating ergolines with alkyl halides or sulfates are known. U.S. Pat. Nos. 3,183,234 and 3,580,916 disclose a procedure for alkylating dihydrolysergic acid in liquid ammonia in the presence of sodium amide and the alkylating agent. This procedure provides the desired product in lower yield less reproducibly than the process disclosed herein.
The present process permits the alkylation of the nitrogen atom at the 1-position of dihydrolysergic acid with a sterically hindered alkyl group employing substituted benzenesulfonate. The use of substituted benzenesulfonate reduces the rate of the competing elimination reaction which produces the undesired olefinic derivative.